Nadean Zahra

Background: Radiation-induced coronary artery disease (RICAD) is a growing cardiovascular disease seen in those who use thoracic radiotherapy, such a breast cancer survivors.¹ Unlike traditional coronary artery disease (CAD), RICAD is has diffuse fibrotic plaque formation at proximal and ostials. RICAD is a diagnostic challenge because of its long and silent latency period as patients can be asymptomatic for 10 to 25 years.² It is the second most common cause of morbidity and mortality in radiotherapy-treated cancer survivors, exceeded only by the primary malignancy.^1,2 Standard cardiac risk calculators do not account for radiation exposure. Current revascularization strategies including percutaneous coronary intervention and coronary artery bypass grafting, however with poor outcomes due to its unique fibrotic characteristics.^3,4 No RICAD-specific targeted therapy currently exists, but a mechanistic understanding of RICAD development is critical to identifying therapeutic targets and enabling early pre-symptomatic detection.²

Objective: In this step-by-step review, we explored the mechanisms by which RICAD starts and develops through the inflammation pathway and discuss potential prevention and monitoring.

Search Methods: An online search in the PubMed database was conducted from 2020 to 2025 using the following keywords: “radiation-induced coronary artery disease”, “RICAD”, “endothelial senescence”, “senescence-associated secretory phenotype (SASP)”, “p90RSK”, “ERK5”, “NF-κB”, “PKCδ”, “VSMC senescence”, “IRF3”, “STING pathway”, “radiomics,” “dosiomics”, and “cardiotoxicity prediction.”

Results: RICAD has three interconnected pathways: DNA damage, oxidative stress, and central to this mechanistic review is chronic inflammation. The initiation is illustrated by Vu et al. ionizing radiation of activating p90RSK which phosphorylates ERK5. This suppresses ERK5’s protective transcriptional activity; instead releasing NF-κB upregulating VCAM-1 inducing endothelial apoptosis in disturbed-flow regions in RICAD.⁵ The path continues following Soroush et al. downstream as these adhesion molecule drives a 20-fold increase in neutrophil transmigration across the endothelial barrier, mediated by PKCδ. PKCδ inhibition restored barrier integrity and reduced leukocyte extravasation, posing a potential therapeutic target.⁶ Continuing downstream, Yamamoto et al. strongly connects in ApoE⁻/⁻ mice that radiation-induced endothelial senescence and SASPs synergize in disturbed flow accelerating atherosclerotic plaque formation, setting SASP as a mechanistic link between radiation exposure and accelerated atherosclerosis.⁷ Further downstream of the SASP, Kaistha et al. demonstrated SASP spreads to VSMCs, where STING/TBK1/IRF3 pathway activation blocks TGF-β-mediated re-differentiation, turning VSMCs into a fibromyocytic phenotype, creating RICAD’s treatment-resistant fibrotic plaque morphology.⁸ Translating these findings, Dincer et al. integrated radiomic to capture early structural changes such as density, thickness, dosimonic, and clinical data to machine learning predicting subclinical cardiotoxicity with an AUC of 0.96 compared to current dosiomic-only models with an AUC of 0.67.^9,10,11 This poses the clinical impact on integrating radiomics in the early detection in the silent progression of RICAD.^9,10,11

Conclusions: RICAD develops through a coordinated inflammatory molecular sequence starting with p90RSK driven endothelial activation down to VSMC fibromyocytic phenotyping giving it its unique morphology. Promising future research, such as dose-fractionation, pathway therapeutic targets, and radiomic prediction models are underway to understand and prevent RICAD.

Work Cited:

1. da Silva RMFL. Effects of Radiotherapy in Coronary Artery Disease. Curr Atheroscler Rep. 2019;21(12). doi:10.1007/s11883-019-0801-9
2. Brown KN, Hussain K, Richards JR. Radiation-Induced Coronary Artery Disease. StatPearls. 2025.
3. Daher J, Rizza A, Tonacci A, Borghini A. A Comprehensive Review of Radiotherapy-Induced Coronary Artery Disease. Int J Mol Sci. 2025;26(11):5401. doi:10.3390/ijms26115401
4. Venkatesulu BP, Mahadevan LS, Aliru ML, et al. Radiation-Induced Endothelial Vascular Injury: A Review of Possible Mechanisms. JACC Basic Transl Sci. 2018;3(4):563-572.
5. Vu HT, Kotla S, Ko KA, et al. Ionizing Radiation Induces Endothelial Inflammation and Apoptosis via p90RSK-Mediated ERK5 S496 Phosphorylation. Front Cardiovasc Med. 2018;5:23.
6. Soroush F, Tang Y, Zaidi HM, Sheffield JB, Kilpatrick LE, Kiani MF. PKCδ inhibition as a novel medical countermeasure for radiation-induced vascular damage. FASEB J. 2018. doi:10.1096/fj.201701099
7. Yamamoto Y, Minami M, Yoshida K, et al. Irradiation Accelerates Plaque Formation and Cellular Senescence in Flow-Altered Carotid Arteries of Apolipoprotein E Knock-Out Mice. J Am Heart Assoc. 2021;10(14):e020712.
8. Kaistha A, Oc S, Garrido AM, et al. Premature cell senescence promotes vascular smooth muscle cell phenotypic modulation and resistance to re-differentiation. Cardiovasc Res. 2025;121(9):1448-1463.
9. Yang EH, Marmagkiolis K, Balanescu DV, et al. Radiation-Induced Vascular Disease—A State-of-the-Art Review. Front. Cardiovasc. Med. 2021; 8:652761. doi: 10.3389/fcvm.2021.652761
10. Dincer S, Akmansu M, Akyol O. Machine learning modeling of cancer treatment-related cardiac events in breast cancer: utilizing dosiomics and radiomics. Front Oncol. 2025;15:1557382.
11. Talebi A, Bitarafan-Rajabi A, Alizadeh-asl A, et al. Machine learning based radiomics model to predict radiotherapy induced cardiotoxicity in breast cancer. J Appl Clin Med Phys. 2025;26:e14614. https://doi.org/10.1002/acm2.14614